The elevation of apoB-containing lipoproteins (VLDL and LDL) in the bloodstream is a risk factor for the development of atherosclerosis. My research goal is to identify the mechanism of the development of hyperlipidemia and hypertriglyceridemia-associated cardiovascular diseases and find therapeutic targets to prevent or delay the progress of the conditions. Hyperlipidemia-induced oxidative stress and the accumulation of oxidized phospholipids in the vessel wall are key events for the development of chronic inflammatory diseases like atherosclerosis and aneurysm. These vascular diseases are accompanied by proinflammatory cytokine overexpression and infiltration of monocytes and macrophages into the vessel wall. Oxidized phospholipids, as represented by Ox-PAPC, strongly activate vascular endothelial cells for the expression of proinflammatory and prothrombotic gene expressions. First, we test the hypothesis that the oxidized phospholipids employ both receptor and non-receptor cytosolic signaling and epigenetic modification for the induction of proinflammatory and prothrombotic gene expressions in the vascular endothelial cells. For the study, we employ in vitro vascular endothelial cell system and in vivo mouse hyperlipidemic model systems (LDLR or ApoE null) with biochemical and (epi)genetics approaches to find a key regulatory pathway and pharmacological target. As a second lab project, we study the role of heparin-binding epidermal growth factor-like growth factor (HB-EGF) signaling in regulating the hepatic and adipose tissue lipoprotein and lipid metabolism during the development of the metabolic syndrome development. Obesity is a key risk factor for the development of metabolic syndrome including insulin resistance, dyslipidemia, and non-alcoholic fatty liver disease (NAFLD). The expression of HB-EGF was upregulated in the adipose tissues under obesity, and the factor is a representative mediator for the sustained EGFR transactivation under various stress-inducing factors like lipid peroxidation products in the tissue of oxidative stress. We hypothesize that the HB-EGF signaling is an unappreciated regulator of hepatic lipoprotein (VLDL) production/secretion and a potential target for lipid-lowering in circulation. HB-EGF targeting antisense oligonucleotide (ASO) showed a remarkable suppression of circulatory triglyceride and cholesterol and the development of atherosclerosis and aneurysm in the vascular wall. We also newly observed that the HB-EGF targeting improved insulin sensitivity in the obese mouse model, suggesting a central role of the HB-EGF in regulating insulin sensitivity in the peripheral tissues. In further studies, we will identify the cellular and molecular mechanism of HB-EGF signaling for the increase of assembly/secretion of VLDL in the liver and evaluate the HB-EGF targeting to prevent metabolic syndrome phenotypes. We employ liver- and adipose-specific HB-EGF knockout mouse systems and liver cell system for this study. We also test the effects of HB-EGF signaling and targeting in the development and progress of phenotypes of fatty liver disease and hepatic inflammation.